The current warfare and terrorist activities around the world, in particular directed against the American people and infrastructure, necessitates a vastly enhanced defense against potential weapons of mass destruction. Among the most lethal and readily deployed means that must be considered are the various toxins of biological origin. In this regard, an often cited scenario is the use of botulinum toxin (BoTox), the causative agent of the clinical condition of botulism, which can have a high fatality rate by either oral consumption or inhalation. New and improved methods of rapidly and conveniently detecting small amounts of BoTox in its various forms are needed, as well as therapeutics for protection against its deadly effects. We propose "biocombinatorial strategies" developed in our laboratory, which refer to human antibodies and cyclic peptides derived from novel phage-display libraries using various selection techniques, against the threat of BoTox. Each of these biotechnological reagents could serve for diagnostic and medicinal purposes, in other words, for detection and/or protection. Specifically, we will use our proprietary antibody and peptide libraries for (1) selection of antibodies and cyclic peptides against BoTox by routine panning, (2) selection of antibodies and cyclic peptides against BoTox by BIAcore panning, (3) characterization of selected antibodies and cyclic peptides by ELISA, (4) characterization of selected antibodies and cyclic peptides using BIAcore, (5) detection of trace amounts of BoTox using antibodies/peptides and BIAcore, and (6) evaluation of selected antibodies and cyclic peptides using the PC12 cell line. The research described provides a foundation for highly sensitive detection and monitoring of BoTox in progenitor and toxic forms and for passive immunotherapy against the active toxin.